Irby Rosalyn B, Yeatman Timothy J
Department of Surgery and Interdisciplinary Oncology Program, Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, Florida 33612, USA.
Cancer Res. 2002 May 1;62(9):2669-74.
Src has been implicated in the development and progression of human colon cancer. Because the capacity for tumor cells to dissociate from the primary tumor is a critical step in the development of metastases, the effect of a naturally occurring, activated Src-531 on intercellular adhesion was examined. Homotypic adhesion was assessed using dissociation assays on Src-transformed rat fibroblasts and human colon cancer cell lines. The data indicate that both rodent and human cells expressing the mutant Src protein display up to 7-fold less homotypic adhesion than do wild-type cells (P < 0.01). Experiments demonstrated that cadherin was phosphorylated in cells transfected with activated Src and that cadherin/catenin complexes were disrupted as a result. Experiments using dominant negative (DN) Src or an Src-specific inhibitor (PD 180970), demonstrated that adhesion was restored when Src activity was inhibited in Src-531 transfectants, confirming that Src is a causal factor in the decreased homotypic adhesion observed. In addition, DN Ras, DN focal adhesion kinase (FAK), but not Stat3beta, restored intercellular adhesion, which suggested that Ras and FAK may be downstream effectors of Src-mediated homotypic adhesion. Collectively, these data support a role for Src, Ras, and FAK in the regulation of intercellular adhesion, which may in turn regulate metastatic potential of human colon cancer cells.
Src与人类结肠癌的发生和发展有关。由于肿瘤细胞从原发肿瘤解离的能力是转移发生过程中的关键步骤，因此研究了天然存在的活化Src-531对细胞间黏附的影响。使用Src转化的大鼠成纤维细胞和人结肠癌细胞系的解离试验评估同型黏附。数据表明，表达突变型Src蛋白的啮齿动物和人类细胞的同型黏附比野生型细胞低7倍（P < 0.01）。实验表明，在转染活化Src的细胞中钙黏蛋白被磷酸化，结果导致钙黏蛋白/连环蛋白复合物被破坏。使用显性负性（DN）Src或Src特异性抑制剂（PD 180970）的实验表明，在Src-531转染细胞中抑制Src活性时黏附得以恢复，证实Src是观察到的同型黏附降低的一个因果因素。此外，DN Ras、DN黏着斑激酶（FAK）而非Stat3β可恢复细胞间黏附，这表明Ras和FAK可能是Src介导的同型黏附的下游效应器。总体而言，这些数据支持Src、Ras和FAK在调节细胞间黏附中的作用，这反过来可能调节人结肠癌细胞的转移潜能。
